The goal of this project is to develop a novel human monoclonal antibody-targeted small interfering RNA (siRNA) therapeutic that has the potential to be first-in-its-kind for treating tumor and metastasis. We have previously identified a panel of rapidly internalizing human single chain antibodies (scFvs) that target clinically represented tumor cell surface antigens. These scFvs were selected from phage antibody display libraries using laser capture microdissection for their ability to bind to tumor cells in situ residing in thir tissue microenvironment, and to mediate efficient intracellular payload delivery to tumor cells. We have in addition identified novel siRNA binding motifs that can be joined with our internalizing scFv and produced as a fusion protein that gains the tumor-targeted intracellular siRNA delivery functions. We propose to develop a novel class of scFv-targeted siRNA therapeutics based on our rapidly internalizing human scFv linked via the novel siRNA binding motif to siRNAs that target genes critical for tumor cell survival.